Identification of Three Endotypes in Pediatric Acute Respiratory Distress Syndrome by Nasal Transcriptomic Profiling

ABSTRACT

1Acute respiratory distress syndrome (ARDS) and pediatric ARDS (PARDS) can be triggered by multiple pulmonary and non-pulmonary insults and are the source of substantial morbidity and mortality. The nasal and lower conducting airways have similar cell composition and nasal transcriptomes identify disease state and sub-classes in lung cancer, COPD, and asthma. We conducted an observational, prospective trial to determine whether this technique could identify PARDS endotypes in 26 control and 25 PARDS subjects <18 admitted to the pediatric ICU. RNA from inferior turbinate brushing was collected on days 1, 3, 7, and 14. Standard RNA-processing yielded 29% usable specimens by mRNA-Seq, and a low-input protocol increased yield to 95% usable specimens. 64 low-input specimens from 10 control and 15 PARDS subjects were used for model development. Control and some PARDS subjects clustered together in Group A while some day 1, 3, and 7 specimens clustered into Groups B and C with specimens from these subjects moving to Group A with PARDS resolution. In multivariate analysis, the only clinical variables associated with specimen Group B or C assignment was severity of lung injury or viral PARDS trigger. Compared to Group A, Group B had upregulation of innate immune processes and Group C had upregulation of ciliary and microtuble processes. Analysis of the 15 standard processing specimens identified the same grouping. Mortality trended higher in group B (25%) and C subjects (28.6%) compared to A (5%, p=0.1). Comparison of groups with 16 PARDS-associated serum biomarkers identified correlation of Endotype B with Tumor Necrosis Factor-, but not other inflammatory cytokines and Endotype C with Surfactant Protein D. We identified three nasal transcriptomic PARDS endotypes. A is similar to control. B is marked by an innate immune signature only weakly reflected in the serum. C may be associated with loss of epithelial barrier integrity. Nasal transcriptomics may be useful for prognostic and predictive enrichment in future PARDS trials. ClinicalTrials.gov Identifier NCT03539783